The candidate, Dr. Preeti Kishore, is a physician scientist with excellent clinical and research training in diabetes. She has over three years experience in performing the research protocols proposed in this application under the mentorship of Dr. Meredith Hawkins and has shown a clear commitment to clinical research. The goal of this application is to help Dr. Kishore establish herself as an independent and productive clinical investigator. Building upon the strong foundation of her Master's in Clinical Research Methods, Dr. Kishore will pursue specifically tailored coursework and regular mentoring sessions by Dr. Hawkins and co-mentors to achieve this goal. The research project will use state-of-the-art magnetic resonance (MR) and insulin 'clamp'methodologies to explore questions of considerable relevance to type 2 diabetes mellitus (T2DM). Endogenous glucose production (EGP) is elevated in T2DM, and is the main cause of fasting hyperglycemia. While rising glucose levels rapidly suppress EGP in nondiabetic individuals, T2DM is associated with loss of the suppressive effects of glucose on EGP. Little is known about the pathogenesis of this loss of 'glucose effectiveness'in T2DM. Although T2DM is known to be associated with increased gluconeogenesis and decreased glycogenolysis, the impact of hyperglycemia on these pathways has never been examined in T2DM subjects. Pancreatic 'clamp'studies, radio-labeled and stable isotope tracers, and MR spectroscopy will be used to study the impact of hyperglycemia on hepatic glucose fluxes. Of note, the chronically elevated free fatty acid (FFA) levels in T2DM may impair hepatic glucose effectiveness. We will therefore evaluate the effects of lowering FFA levels in T2DM on the regulation of hepatic glucose fluxes. Given the importance of the loss of hepatic 'glucose effectiveness'to worsening hyperglycemia in T2DM, elucidating these relationships would be of considerable therapeutic relevance.